Inflammation is one of the immune system’s most important defenses. When the body detects an infection or injury, it sends out alarm signals that recruit immune cells and other cells to eliminate the threat and begin repairing damaged tissue.
This response is essential, but it is supposed to shut down once the danger has passed. As people age, however, certain cells accumulate that can keep inflammation active for much longer than necessary. This persistent inflammation has been associated with numerous diseases that become more common later in life.
Researchers at Sanford Burnham Prebys Medical Discovery Institute, Mayo Clinic, and collaborating institutions have now uncovered a previously unknown connection between mitochondria, cell metabolism, and this chronic inflammation. Their findings, published in Nature, also showed that interfering with part of the process reduced inflammation and supported healthier aging in mice.
How “Zombie” Cells Accumulate With Age
Many cells in the body are capable of dividing, allowing us to grow and helping tissues repair themselves after injury. But as we get older, increasing numbers of cells enter a state known as senescence. These zombie-like senescent cells stop dividing, yet they remain alive and active.
“Senescent cells are not completely inert,” said co-corresponding author Peter Adams, PhD, the Jeanne and Gary Herberger Leadership Chair in Cancer Research at Sanford Burnham Prebys. Adams also is director of and professor in the Cancer Genome and Epigenetics Program.
“They remain metabolically active and have an inflammatory program causing them to secrete inflammatory molecules.”
When senescent cells activate this inflammatory program, they are described as having the senescence-associated secretory phenotype (SASP). SASP has been linked to widespread inflammation associated with aging as well as a range of chronic diseases.
The research team, led by the laboratory of senior and co-corresponding author João Passos, PhD, a professor of Physiology at Mayo Clinic, set out to identify the molecular processes that drive SASP. Their broader goal was to determine whether those processes might be interrupted or reduced.
“It turns out that there is a convergence of at least two biological pathways related to mitochondria,” said Adams. “One alters how DNA is stored to promote areas related to SASP, and the other boosts the expression of the exposed SASP genes.”
Mitochondria Help Unlock Inflammatory Genes
Although senescent cells no longer divide, they continue using energy and carrying out metabolic activity. The researchers found that their mitochondria, the structures responsible for much of a cell’s energy production, behave differently from those in healthier cells.
In particular, mitochondria in senescent cells produced increased amounts of acetyl-CoA, an important molecule involved in metabolism.
Acetyl-CoA also interacts with histones, spool-like proteins around which DNA is wrapped. By altering these histones, acetyl-CoA can loosen the way DNA is packaged. This does not change the genetic code itself. Instead, it makes certain genes more accessible, including genes involved in the inflammatory SASP response.
That metabolic change alone, however, was not enough to explain why senescent cells continuously release inflammatory molecules.
Two Mitochondrial Signals Work Together
A second process was also required.
Damaged mitochondria can leak DNA and RNA into parts of the cell where those molecules normally should not be present. The immune system interprets this misplaced genetic material as a danger signal, triggering an inflammatory response.
These immune signals activate transcription factors that help switch genes on. Those factors are then able to target the SASP genes that have already been made more accessible by elevated acetyl-CoA.
In other words, the researchers found that two separate mitochondrial processes converge. One exposes inflammatory genes, while the other provides the immune signal needed to activate them.
“After seeing how these two independent pathways intersect, we wanted to see if interrupting one could prevent their partnership in promoting SASP,” said Adams.
Blocking the Metabolic Signal Reduced Inflammation
To test that possibility, the researchers used a drug called CTPI-2. The drug blocks a transport protein responsible for carrying a component needed to produce acetyl-CoA.
When CTPI-2 was tested in mice, it reduced inflammation throughout multiple tissues. The treatment also improved tissue function and healthspan during aging.
Importantly, the immune signals caused by leaking mitochondrial DNA and RNA were still present. But by weakening the metabolic signal involving acetyl-CoA, the researchers made SASP genes more difficult to access and reduced their inflammatory effects.
“Even though the immune signaling from leaky mitochondria was still present, disrupting the metabolic signal made SASP genes less accessible and produced functional benefits,” said Adams. “Using selective inhibitors such as CTPI-2 to reduce acetyl-CoA and, in turn, inflammation is a novel therapeutic strategy that should be explored.
“Also, more broadly, this research shows that targeting metabolic signals that influence DNA accessibility may represent a new approach for mitigating age-associated inflammation and functional decline.”
The findings suggest that changing the metabolic signals controlling access to inflammatory genes could offer a new strategy for addressing chronic inflammation and declining tissue function during aging.
Hélène Martini, PharmD, PhD, a postdoctoral researcher in the Passos lab at Mayo Clinic, is first author of the publication.
Additional authors include:
- Aaron Havas, Rabi Murad, Xue Lei and Rebecca A. Porritt at Sanford Burnham Prebys
- Anthony B. Lagnado, Nicholas Pirius, Ana Catarina Franco, Gung Lee, Yeaeun Han, Jennifer L. Rowsey, Stella Victorelli, Wazim Mohammed Ismail, Amelia Mazzone, Tianna M. Espe, Taro Hitosugi, Ya Li, Alexander M. Washington, Jair Machado Espindola-Netto, Dominik Saul, Sundeep Khosla, Diana Jurk, Enis Kostallari and Alexandre Gaspar-Maia at Mayo Clinic
- Jodie Birch at Imperial College London
- Francisco D. M. Marques at Albert Einstein College of Medicine
- Oliver D. K. Maddocks at the University of Glasgow
The study was supported by the National Institutes of Health, National Institute on Aging, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, Department of Defense Ovarian Cancer Research Program, Hevolution Foundation, The Glenn Foundation for Medical Research, Cancer Research UK, and Robert and Arlene Kogod Center on Aging.
